New use, pharmaceutical preparations as well as a process for their production

ABSTRACT

The invention concerns the use of mercaptoethane sulfonate-sodium (Mesna) to increase the solubility of Ifosfamide in storage-stable, concentrated and/or highly-concentrated (supersaturated) aqueous pharmaceutical preparations, storage-stable, concentrated and/or highly-concentrated (supersaturated) aqueous pharmaceutical Ifosfamide preparations for parenteral administration as well as a process for their production.

This application claims priority from provisional application No.60/505,750 filed on Oct. 1, 2003.

FIELD OF THE INVENTION

The invention concerns the use of mercaptoethane sulfonate-sodium(Mesna) to increase the solubility of Ifosfamide in storage-stable,concentrated and/or highly-concentrated (supersaturated) aqueouspharmaceutical preparations, storage-stable, concentrated and/orhighly-concentrated (supersaturated) aqueous pharmaceutical Ifosfamidepreparations for parenteral administration as well as a process fortheir production.

STATE OF THE ART

Ifosfamide(2-(chlorethylamino)-3-(2-chlorethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide)is an alkylating cytostatic agent that is administered against a varietyof tumor-diseases, at times in combination with other cytostatic agents.Mesna (mercaptoethane sulfonate-sodium) is co-administered withIfosfamide in order to reduce the side-effects of Ifosfamide (c.f. U.S.Pat. Nos. 4,770,870 and 4,220,660; German Patent Application DE2806866).

The solubility of Ifosfamide in water is limited and at room temperatureis a maximum of about 140 mg/mL (saturation concentration). The additionof auxiliary agents can sometimes lower the solubility of Ifosfamide,e.g. to under 10% (wt/vol), so that even at low concentrations, the useof a solubility-enhancing agent is necessary in order to obtain a clear,injectable solution.

A concentrated and/or high-concentrated Ifosfamide solution has criticaladvantages in handling in comparison to a diluted solution. The dosageof Ifosfamide depends upon the body surface or weight of the patient andlies in general between 3 g and 5 g, but can in individual cases also beover 10 g. For exacting preparation of patient-specific dosage, volumesare advantageous that are easily handled and that can be added tostandard infusion solutions. For a concentrated Ifosfamide solution ofe.g. 20% (wt/vol) active ingredient, 15 ml to 25 ml will have to bedosed, which allows for a sufficiently highly precise dosage as well aseasy handling of single injection. In contrast to this, a currentlymarketed Ifosfamide solution of 4% (wt/vol) content must be dosed at 75ml to 125 ml, and in individual cases, as much as 250 ml.

On the basis of the aforementioned limitations of solubility, solutionsof Ifosfamide at concentrations >10% (wt/vol) for parenteral use thatare devoid of particles and crystals are possible only with the additionof a solubility-enhancing agent. Based on the presentation form asinjectable solution, these solubility-enhancing agents must be free fromany physiological concerns. In the state of the art, a urea is suggestedas solubility-enhancing agent (c.f. WO 99/18973). Urea is, however,suspected to increase the neural side-effects of Ifosfamide.

As solubility-enhancing agents, theoretically Tensides such as, e.g.,Tween 80 or Poloxamer can be considered. The ability to use them,however, is limited or in some cases forbidden on account of theirhaemological characteristics.

For this reason there exists a need for storage-stable concentratedand/or highly concentrated pharmaceutical Ifosfamide preparations thatdo not require the addition of urea and/or Tensides.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that through the use of mercaptoethanesulfonate-sodium (Mesna) a highly concentrated (supersaturated) aqueoussolution of Ifosfamide can be successfully prepared, whose concentrationis substantially above the saturation concentration of Ifosfamide inwater. The saturation concentration of about 140 mg/ml at roomtemperature as well as the saturation concentration of about 190 mg/mlat about 5° C. can be surpassed by a wide margin by the use of Mesna. Bythe use of Mesna as solubility-enhancing agent, a storage-stableconcentrate of Ifosfamide can be successfully produced in respect of itsphysical characteristics in a concentration region from about 10%(wt/vol) to 50% (wt/vol).

Solutions with an Ifosfamide content above the aforementioned amountsand concentrations are hereinafter referred to as highly concentratedand/or supersaturated, whereby the term “supersaturated” means that thepreparations according to the invention are storage-stable and free ofprecipitation of Ifosfamide in spite of the high concentration ofIfosfamide.

The use of Mesna as solubility-enhancing agent in the production ofconcentrated and/or highly concentrated Ifosfamide solutions is neitherdescribed in nor suggested by the state of the art.

The use of Mesna according to the invention enables the production ofaqueous concentrates of the active agent Ifosfamide in concentrationsabove the saturation concentration of Ifosfamide in water, i.e. greaterthan 10% (wt/vol), using Mesna as a solubility-enhancing agent forIfosfamide. Preferably, preparations with Ifosfamide concentrationsgreater than 10% (wt/vol) up to 50% (wt/vol) are formed. At the sametime, solution temperatures are selected between 0° C. and 30° C.,preferably 2° C. and 20° C., especially preferred 5° C. and 15° C.

The production of concentrates is brought about by dissolving therequired amount of Mesna, e.g. 5 g to 50 g per 100 ml, preferably 10 gto 20 g per 100 ml and optionally a suitable buffer (phosphate, borate,carbonate buffer, preferably phosphate buffer) in Water for Injection(WFI), subsequently the corresponding quantity of Ifosfamide is added toa room temperature or preferably cooled solution of Mesna, whereby theratio of Ifosfamid to Mesna is from 1:0.25 to 1:4, preferably 1:0.5 to1:2, more preferably 1:0.8 to 1:1.2, most preferably 1:1.0 to 1:1.2. Theratios refer to the proportions by weight of the substances in thesolution. The solutions are homogenized, sterilized by filtration andfilled under aseptic conditions. Production is carried out undernitrogen. These solutions can also be lyophilized in order to obtain alonger storage life of the pharmaceutical preparation. In addition tothe auxiliary agents that are set forth in the examples, the solutioncan contain also further substances, e.g. sodium chloride, Mannitol,lactose, polyethylenglycol, ethanol, glucose, disaccharide,cyclodextrine.

The term “cooled” solution temperatures means from about 0° C. to aboutbelow room temperature (below about 21° C.), preferably from about 2° C.to lower than or equal to about 20° C., more preferably from about 5° C.to about 15° C., still more preferably from about 5° C. to about 10° C.

The invention will be more specifically demonstrated by the followingexamples, but should not be restricted to them.

EXAMPLE 1

Ifosfamide Concentrate 20% (wt/vol) with 20% (wt/vol) Mesna Content

Composition of the Solution: Ifosfamide 2000.0 mg Mesna 2000.0 mgPhosphate buffer 1000.0 mg Water (WFI) 6540.0 mg

In the manufacture, 90% of the Water for Injection is cooled to about 5°C. to 10° C., to which is dissolved the phosphate buffer; the Mesna issubsequently added and is homogeneously dissolved. Finally, theIfosfamide in the solution is dissolved and the pH is set at 7.4 withortho-phosphoric acid. The solution so obtained is brought to thespecified weight with the cooled Water for Injection, sterile-filteredand filled in injection vials under aseptic conditions. Sterilizationand filling are not carried out under cooling.

EXAMPLE 2

Ifosfamide Concentrate 20% (wt/vol) with 5% (wt/vol) Mesna

Composition of the Solution: Ifosfamide 2000.0 mg Mesna  500.0 mgPhosphate buffer 1000.0 mg Water (WFI) 8040.0 mg

The solution is produced identically according to the procedure ofExample 1.

EXAMPLE 3

Ifosfamide Concentrate 20% (wt/vol) with 5% (wt/vol) Mesna, Lyophilisateand Reconstituion of the Lyophilisate:

Composition of the Solution Before Filling and After Reconstitution:Ifosfamide 2000.0 mg Mesna  500.0 mg Mannitol  500.0 mg Water (WFI)8040.0 mg

In the manufacture, added to about 90% of the Water for Injection thatis pre-cooled to about 5° C. to 10° C. is, sequentially, the Mesna, theIfosfamide and the Mannitol, whereby each is homogenized until a clearsolution is obtained. Subsequently, the solution is sterile filtered andfilled under aseptic conditions in injection vials to the specifiedweight for lyophilisation. Lyophilization ensues with a suitablefreeze-dry device and lyophilization process, e.g. Freezing   1 hour at−45° C. 3.5 hours maintained at −45° C. Main drying 0.4 mbar, in 1.5hours from −45° C. to −15° C. 0.4 mbar, 120 hours at −15° C. Post drying0.4 mbar, increasing over 4 hours to 20° C. Max. vacuum, 6 hours at 20°C.

The injection vials are sealed shut under nitrogen.

Composition of the Lyophilisate: Ifosfamide 2000.0 mg  Mesna 500.0 mgMannitol 500.0 mg

Reconstitution of the Lyophilisate:

For reconstitution, the lyophilisate is mixed with 8 ml Water forInjection or with a suitable infusion solution, e.g. isotonic saltsolution, glucose solution for infusion, Ringer lactate soltution, etc.so that an approximately 20% (wt/vol) solution of Ifosfamide is formed.This concentrate can then be used by individual dosage as an additivefor an infusion preparation. The production of a lyophilisate and itsreconstitution can then ensue with the addition of an auxiliary agent,such as Mannitol, glucose, disaccharide or a similar lyophilisate fillerknown in the art.

EXAMPLE 4

12% (wt/vol) Ifosfamide Concentrate with 5% (wt/vol) Mesna Ifosfamide:  3 g Mesna: 1.25 g Water: 24.5 g

EXAMPLE 5

25% (wt/vol) Ifosfamide Concentrate with 10% (wt/vol) Mesna Ifosfamide: 6.25 g Mesna:  2.5 g Water: 23.75 g

EXAMPLE 6

50% (wt/vol) Ifosfamide Concentrate with 20% (wt/vol) Mesna Ifosfamide:12.5 g Mesna:  5.0 g Water: 17.5 g

The making of Examples 4, 5 and 6 is carried out analogously to thedescription of Example 1. The solubility-enhancing properties of Mesnain respect of Ifosfamide are demonstrated over a wide range ofconcentrations and proportions. The addition of a buffer, e.g. phosphatebuffer, largely does not influence the solubility-enhancement, thebuffering addition being however necessary for the chemicalstabilization of the preparation in order to minimize decomposition ofthe active agent and in order to obtain sufficient storability of thesolution. Apart from that, the Mesna provides as solubility-enhancingagent a physical stabilization that prevents crystallization.

1. The use of Mesna for improving the solubility of Ifosfamide in anaqueous pharmaceutical preparation with a content of Ifosfamide of morethan 10% (wt/vol) (storage-stable concentrated and/or highlyconcentrated aqueous pharmaceutical Ifosfamide preparation) in respectof the total weight of the preparation, and optionally containing one ormore pharmaceutically acceptable auxiliary agents.
 2. The use of Mesnaaccording to claim 1, characterized in that the weight ratio ofIfosfamide to Mesna is in the range of 1:0.25 to 1:4, preferably 1:0.8to 1:1.2, more preferably 1:1.
 3. The use according to claim 1 or 2,characterized in that the auxiliary agent is selected from the groupconsisting of one or more buffers, sodium chloride and Mannitol.
 4. Theuse according to one of claims 1 to 3, characterized in that the pH isset at pH 6-8 by way of a suitable buffer.
 5. A storage-stabileconcentrated and/or highly concentrated (supersaturated) aqueouspharmaceutical preparation for parenteral administration containingIfosfamide in an amount greater than 10% (wt/vol) and Mesna, in respectof the amount by weight of Ifosfamide present, in a weight ratio of 1:1to 1:4, and optionally containing one or more pharmaceuticallyacceptable auxiliary agents.
 6. A storage-stabile concentrated and/orhighly concentrated aqueous pharmaceutical preparation according toclaim 5, characterized in that the pH is set at pH 6-8 by way of asuitable buffer.
 7. A lyophilisate for reconstitution of a concentratedand/or highly concentrated (supersaturated) aqueous pharmaceuticalpreparation for parenteral administration containing Ifosfamide in anamount greater than 10% (wt/vol) and Mesna, in respect of the amount byweight of Ifosfamide present, in a weight ratio of 1:1 to 1:4, andoptionally containing one or more pharmaceutically acceptable auxiliaryagents.
 8. A lyophilisate according to claim 7, characterized in thatthe pH after reconstitution of the concentrated and/or highlyconcentrated aqueous pharmaceutical preparation is set at pH 6-8 by wayof a suitable buffer.
 9. A process for the production of astorage-stable concentrated and/or highly concentrated (supersaturated)aqueous pharmaceutical preparation for parenteral administrationcontaining Ifosfamide in an amount greater than 10% (wt/vol) and Mesna,in respect of the amount by weight of Ifosfamide present, in a weightratio of 1:1 to 1:4, and optionally containing one or morepharmaceutically acceptable auxiliary agents, characterized in the steps(1) adding Mesna to a portion of Water for Injection, preferably 90% ofthe total amount of water, (2) adding Ifosfamide and (3) adding theremainder of Water for Injection.
 10. The process according to claim 9,characterized in that the water used is at a temperature ranging fromabout 0° C. to under room temperature (about 21° C.), preferably about2° C. to lower than or equal to about 20° C., more preferably about 5°C. to about 15° C., still more preferably about 5° C. to about 10° C.11. The process according to claim 9 or 10, characterized in that theoptional one or more auxiliary agents is added entirely or in portionsbefore, during or after the steps (1), (2) and (3).
 12. The processaccording to any one of claims 9 to 11, characterized in that theso-obtained preparation is sterile-filtered and filled under asepticconditions in one or more suitable containers.
 13. A process for theproduction of a lyophilisate for reconstitution of a concentrated and/orhighly concentrated (supersaturated) aqueous pharmaceutical preparationfor parenteral administration containing Ifosfamide in an amount greaterthan 10% (wt/vol) and Mesna, in respect of the amount by weight ofIfosfamide present, in a weight ratio of 1:1 to 1:4, and optionallycontaining one or more pharmaceutically acceptable auxiliary agentscharacterized in the steps of (1) adding Mesna to a portion of Water forInjection, preferably 90% of the total amount of water, (2) addingIfosfamide, (3) adding the remainder of Water for Injection and (4)lyophilizing the so-obtained preparation.
 14. The process according toclaim 13, characterized in that the water used is at a temperatureranging from about 0° C. to under room temperature (about 21° C.),preferably about 2° C. to lower than or equal to about 20° C., morepreferably about 5° C. to about 15° C., still more preferably about 5°C. to about 10° C.
 15. The process according to claim 13 or 14,characterized in that the optional one or more auxiliary agents is addedentirely or in portions before, during or after the steps (1), (2) and(3).
 16. The process according to any one of claims 13 to 15,characterized in that before step (4) the preparation issterile-filtered and under filled aseptic conditions in one or moresuitable containers.
 17. A process for the production of a concentratedand/or highly concentrated (supersaturated) aqueous pharmaceuticalpreparation for parenteral administration containing Ifosfamide in anamount greater than 10% (wt/vol) and Mesna, in respect of the amount byweight of Ifosfamide present, in a weight ratio of 1:1 to 1:4, andoptionally containing one or more pharmaceutically acceptable auxiliaryagents characterized in the steps of (1) adding Mesna to a portion ofWater for Injection, preferably 90% of the total amount of water, (2)adding Ifosfamide, (3) adding the remainder of Water for Injection, (4)lyophilizing the so-obtained preparation in its entirety or in suitableportions and immediately or at a later time adding a desired amount ofWater for Injection to obtain the concentrated (supersaturated)pharmaceutical preparation.
 18. The process according to claim 17,characterized in that the water used is at a temperature ranging fromabout 0° C. to under room temperature (about 21° C.), preferably about2° C. to lower than or equal to about 20° C., more preferably about 5°C. to about 15° C., still more preferably about 5° C. to about 10° C.19. The process according to claim 17 or 18, characterized in that theoptional one or more auxiliary agents is added entirely or in portionsbefore, during or after the steps (1), (2) and (3).
 20. The processaccording to any one of claims 17 to 19, characterized in that beforestep (4) the preparation is sterile-filtered and under filled asepticconditions in one or more suitable containers.
 21. Ifosfamideconcentrate produced or producible according to the process of one ofclaims 9 to
 12. 22. Ifosfamide lyophilisate produced or producibleaccording to the process of one of claims 13 to
 16. 23. Ifosfamidereconstitute produced or producible according to the process of one ofclaims 17 to 20.